3-substituted-1-phenyl-indolines and indolinones in composition for alleviating mentol depression

ABSTRACT

Novel 3-mono-aminoalkyl-1-phenyl-indolines and 2-indolinones are disclosed.

United States Patent Canals-Rodriguez et al. l 1March 13, 19733-SUBSTITUTED-l-PHENYL- [52] US. Cl. ..424/274, 424/248, 424/250,INDOLINES AND INDOLINONES IN 424/267 COMPOSITION FOR ALLEVIATING [5 1]Int. Cl. ..A61v 27/00 MENTOL DEPRESSION [58] Field of Search ..424/248,250, 267, 274

[75] Inventors: Antonio Canas-Rodriguei, Peter I Rodway Leeming, both ofCanter- [5 6] References Clted bury Kent England UNITED STATES PATENTS[73] Assignee: Pfizer Inc., New York, NY. 3,184,466 5/1965 Henni et al...260/326.1l X r r 3,468,907 9/1969 Sherlock ..260/326. I 2 [22] Filed:Feb. 14, 1972 v [21] Appl. No.: 226,291 Primary Examiner-Stanley J.Friedman Attorney-Connolly and Hutz Related [1.8. Application Data [62]Division ofSer. N0. 885,32l, Dec. 15, 1969,Pat. No. AB RACT Novel3-mono-aminoalkyl-l -phenylindolines and 2- 301 Foreign ApplicationPriority Data are dscmsed- Dec. 18, 1968 Great Britain ..60,083/68 5Claims, No Drawings 3-SUBSTITUTED-l-IIIENYL-INDOLINES AND INDOLINONES INCOMPOSITION FOR ALLEVIATING MENTOL DEPRESSION CROSS-REFERENCE TO RELATEDAPPLICATION This application is a division of application Ser. No.885,321 filed Dec. 15, 1969 now U.S. Pat. 3,644,403.

BACKGROUND OF THE INVENTION This invention relates to certain noveltherapeutic agents. More particularly, it relates to3-monoaminoalkyl-l-phenyl-indolines and 2-indolinones which have usefulanti-depressant actions.

SUMMARY OF THE INVENTION The present invention disclosed compoundshaving the formula:

wherein R and R are each selected from the group consisting of hydrogen,alkyl from one to four carbon atoms, benzyl and R and R when takentogether, complete a ring selected from the group consisting ofpiperidino, pyrrolidino, morpholino, piperazino, N'- benzylpiperazino,N'-alkylpiperazino and N'-hydroxyalkylpiperazino, said alkyl containingfrom one to four carbon atoms; R is selected from the group consistingof hydrogen, nitro and halogen (F, Cl, Br, I); X is selected from thegroup consisting of two hydrogen atoms and an oxygen atom; n is aninteger of from 2 to 4; and pharmaceutically acceptable acid additionsalts thereof.

A particularly preferred embodiment of the above described features ofthis invention concerns these compounds indicated by the above formulawhen R is hydrogen and n is 3.

In addition, there is claimed a method of alleviating mental depressionin a host which comprises administering to the host an effective amountof a compound selected from the group consisting of those with theformula:

wherein R and R are each selected from the group consisting of hydrogen,alkyl of from one to four carbon atoms, benzyl and R and R when takentogether complete a ring selected from the group consisting ofpiperidino, pyrrolidino, morpholino, piperazino, N'- benzylpiperazino,N'-alkylpiperazino and N'-hydroxyalkylpiperazino, said alkyl containingfrom one to four carbon atoms; R is selected from the group consistingof hydrogen, nitro and halogen (F, Cl, Br, I); X is selected from thegroup consisting of two hydrogen atoms and an oxygen atom; n is aninteger of from 2 to 4; and pharmaceutically acceptable acid additionsalts thereof.

The compounds of this invention have marked activity on the centralnervous system of the host which is treated. They have properties incommon with antidepressant drugs. In particular, they antagonize thesedation induced in rats by intraperitoneally injected tetrabenazine,potentiate the response to low frequency electrical stimulation of thenictitating membrane of the cat, potentiate the effects of injectedepinephrine or norepinephrine on the blood pressure of the cat, andreverse the hypothermia caused by intraventricularly injectednorepinephrine in the mouse.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this inventionfall into two distinct classes. The first class concerns3-monosubstituted-l-phenyl-2-indolinones and the second concerns thereduced analogs thereof. More specifically, one method of obtaining thelatter group is by reducing the keto function in the 2-position to amethylene function. There exist several methods for synthesizing theindolinone derivatives, and one mode of preparation for the secondgroup, that is, the indolines, comprises the reduction of the aforesaidindolinones to the corresponding indolines. The aforesaid chemicalreduction can be accomplished by means of hydroboration. The indolinecompounds may also be prepared from 1- phenyI-B-indolinyl carboxylicacids, and also from 3- substituted-l-phenylindoles by reduction of theheterocyclic portion of the indole ring of the latter compounds. Hence,not only are the indolinone compounds useful per se for the utilitydescribed herein, but they are also valuable chemical intermediates forthe preparation of the useful indoline compounds.

A 3-unsubstituted l-phenyl-Z-indolinone of the formula:

may be reacted with an alkali metal (or a hydride, amide or alkoxidethereof) in a suitable solvent, e.g., toluene or dimethylformamide,to'form an alkali metal derivative of the indolinone and then with ahalogenated amine of theformula:

where neither R nor R is hydrogen, to yield a compound of the formula:

However, in this reaction substantial amounts of 3,3 -bis (aminoalkyl)derivatives are formed. We have now discovered that it is preferred touse instead of an alkali metal, either thallium metal or a thallousalkoxide, since under these conditions 3-mono-(aminoalkyl) derivativesare formed.

Use of thallium metal or a thallous alkoxide precludes the formation of3,3-bis (aminoalkyl) derivatives. Previous methods as disclosed inBelgian patent 711,058 required the use of a3-monosubstituted-lphenyl-2-indolinone, whereas this present inventiondiscloses the use of a 3-unsubstituted-l-phenyl-2-indolinone to producea 3-monosubstituted derivative.

The preferred method of synthesis of the indolinone compounds of thisinvention involves dissolving a 1- phenyI-Z-indolinone in a suitableorganic solvent, such as toluene, benzene or dimethylformamide. To thisan equimolar quantity of thallium metal or a thallous alkoxide, such asI thallous ethoxide is added. A precipitate is formed which is thenredissolved in a suitable solvent, such as dimethylformamide. To this isadded a halogenated alkyl amine, such as Sdimethylaminopropyl chloridein equimolar proportions or in a slight excess. The mixture is heatedunder reflux for about 4 to 8 hours. Work-up consists of evaporating offthe solvent, cooling, mixing with water, extracting with ether,separating, drying and evaporating to give product.

The resulting indolinone may be reduced to the corresponding indoline,wherein X is H by the use of diborane as the reducing agent. Theindolinone to be reduced is dissolved in suitable solvent, e.g.,tetrahydrofuran and in a flask fitted with an inlet from a diboranegenerator. The generated diborane is allowed to pass through thesolution for about 3 hours whereupon the resulting solution is thencooled, acidified with N hydrochloric acid, and the solvents are removedleaving an oil which is subsequently extracted with ether and convertedto a suitable acid addition salt such as the hydrogen maleate salt.

Compounds in which X is H, may also be prepared from1-phenyl-3-indolinyl carboxylic acids or alcohols of the formulas:

jqcmxmcoon N by converting the acid (or a suitable'ester thereof) to theappropriate amide by reaction with ammonia or amine of the formula RRNl-l and reducing the amide with lithium aluminum hydride, or byconverting the alcohol to the appropriate amine by reaction of asuitable ester of the alcohol with an amine of the formula R RNH.

l-phenyl-3-indolinyl carboxylic acids and alcohols are prepared from3-indolyl carboxylic acids of the for mula:

T Gua -c0011 I (or suitable esters thereof) by hydrogenation of the acidor ester at a sufficiently high pressure (e.g., 4000 psi) in thepresence of Raney nickel as described by Kornfeld, et. al. in J.Amer.Chem. Soc., Vol. 78, p. 3096 (1956) or at lower pressure in the presenceof a nickel or palladium or platinum catalyst freshly prepared in situ,to yield the corresponding 3-indolinyl carboxylic acid or ester which isthen either phenylated direct by the Ullmann reaction, with a phenylhalide and copper powder, or first reduced with lithium aluminum hydrideto the alcohol and then phenylated.

Compounds in which X is H, may also be prepared from3-aminoalkyl-substituted l-phenyl-indoles of the formula: I

by reduction with sodium in liquid ammonia. In this method, the indolestarting material is dissolved in a suitable solvent, e.g.tetrahydrofuran, the solution is added to liquid ammonia (anhydrous) andsmall pieces of sodium are added until a blue color persists in thesolution for at least several minutes. Ammonium chloride is then addedto decompose the complex productand the ammonia evaporated off. The pureproduct is recovered by evaporating off the solvent, extracting intoether, drying and evaporating off the ether or precipitating as asuitable salt, e.g. the oxalate, by adding an ethereal solution of theappropriate acid.

There exist several process modifications which find application in thepresent disclosure. For instance, it may be possible to convert anN,N-di-substituted amino compound to the corresponding N-monosubstituted derivative. To illustrate, a dimethylamino compound can beconverted to the monomethylamino derivative by treatment with an alkylchloroformate, resulting in an intermediate alkoxycarbonyl derivativefrom which the alkyloxycarbonyl group is subsequently removed byhydrolysis under acidic or basic conditions.

Furthermore, a benzyl moiety attached to the nitrogen of the amino groupmay be converted to hydrogen by hydrogenation in the presence ofpalladium.

Another process modification concerns the placement of varioussubstituents onto the fused benzene ring. For example, treatment of anindoline or 2-indolinone with sulfuryl chloride in glacial acetic acidresults in the formation of the corresponding 5-chloro compound,Similarly, treatment with bromine in glacial acetic acid provides thecorresponding S-bromo compound. Some chlorination or bromination mayalso occur in the 3-position, however, when a 2-indolinone is treated inthis manner, and products of this side reaction may have to beeliminated to obtain the pure 5- substituted 2-indolinone.

The compounds of this invention have the ability to alleviate mentaldepression particularly when administered orally. Additionally, thecompounds of the invention give positive results in tests inexperimental animals designed to show possession of the followingproperties:

1. potentiation of amphetamine excitation.

2. Antagonism of tetrabenazine sedation.

3. Antagonism of reserpine hypothermia.

4. Antagonism of nonepinephrine hypothermia.

5. Potentiation of stimulation of the nictitating membrane.

6. Potentiation of the effect of norepinephrine on blood pressure.

These tests are well established methods for testing potential drugs inorder to indicate whether they possess anti-depressant properties. Tests1 and 2 are carried out in rats via oral administration. Tests 3 and 4are run on mice, wherein test 3 utilizes intraperitoneal administrationand test 4 is by oral administration. The last two, that is, 5 and 6 usethe intravenous mode of administration wherein the host is a cat.

The compounds of the invention exist in D and L optically activeisomeric forms, by virtue of the asymmetric carbon atom at position 3 inthe indoline nucleus, and the invention comprehends the compounds in theseparated D and L forms, as well as the racemic DL- mixtures produced bythe above methods.

Acids from which pharmaceutically-acceptable addition salts of thecompounds of the invention can be prepared are those which formnon-toxic acid addition salts containing pharmaceutically-acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate orbisulfate, phosphate or acid phosphate, acetate, maleate, fumarate,lactate, tartrate, citrate, gluconate, saccharate, and p-toluenesulfonate salts.

The compounds of the invention can be administered along, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they may be administeredorally, preferentially in the form of tablets containing such excipientsas starch or lactose, or in capsules either alone or admixture withexcipients, or in the form of solutions or suspensions containingflavoring or coloring agents. They may be injected parenterally, forexample, intramuscularly or subcutaneously. For parenteraladministration, they are best used in the form of a sterile aqueoussolution which may contain other solutes, for example, enought saltsorglucose to make the solution isotonic.

With respect to dosage levels, a broad dosage range of 5 to 500 mgJdayis appropriate. However, on a body-weight basis, thedosage range wouldbe from about 0.1 to about 5.0 milligrams per kilogram per day. Aparticularly preferred range for adults is from 0.3 to about 3.0mg./kg./day. The physician in any event will determine the actual dosagewhich will be most suitable for an individual patient and it will varywith age, the weight and response of the particular patient. The abovedosages are exemplary of the average host. There can, of course, beindividual cases where higher or lower dosage ranges are merited, andsuch are within the scope of this invention.

EXAMPLE I To l-phenyl-2-indolinone (20.9 g., 0.1 mole) dissolved in hot,dry benzene (200 mls.) thallous ethoxide (24.5 g. 0.1 mole) is added. Oncooling a heavy precipitate of the thallous derivative is obtained. Drydimethylformamide (150 ml.) is added to the mixture followed by3-dimethylaminopropyl chloride, (13.6 g., 0.11 mole), freshly preparedfrom the corresponding hydrochloride and KOH pellets. The mixture isheated to and stirred for 6 hours, after which the solvents areevaporated in vacuo. Traces of dimethylformamide and alkylating reagentare eliminated by azeotropic distillation in vacuo with xylene. Theresidual'oil is treated with water and extracted with ether, and theetheral liquors are filtered through a small layer of active alumina.The ethereal solution is dried and treated with ethereal solution ofanhydrous oxalic acid. A white precipitate is obtained which isthoroughly washed with ether and recrystallized from isopropanol fivetimes to give 2 g. of pure 3-(3dimethylaminopropyD-l-phenyl-2-indolinone oxalate as a white solidcontaining water of crystallization (half a molecule). M. Pt.: l54l55,

Analysis:

Calcd. for: C H NO H O: C, 64.10; H, 6.40; N,

7.29 Found: C, 64.33; H, 6.37; N, 7.08

EXAMPLE II 3-[3-(4-methyl-l-piperazinyl)propyl]-l-phenyl-2-indolinonedihydrogen maleate (From 3-(4-methyll-piperazinyl)propyl chloride),

3-[3-(4-hydroxyethyl-l-piperazinyl)propyl]-l-phenyl-2-indolinonedi-hydrogen maleate (From 3-(4- hydroxyethyl-l-piperazinyl)propylchloride).

3-(3-benzylaminopropyl)-1-phenyl-2-indolinone)hydrgen oxalate (From3-benzylamino propyl chloride).

EXAMPLE Ill 3-(3-dimethylaminopropyl)-l-phenyl-2-indolinone (0.136 mol.)in tetrahydrofuran (400 ml.) is placed in a flask fitted with an inletfrom a diborane generator. The diborane generator is charged with sodiumborohydride (2.5 mol.) and dimethyl digol (600 ml.). After a preliminarypurge of the apparatus for fifteen minutes with nitrogen, the cautiousaddition of boron trifluoride diethyl etherate (3.5 mol.) to thegenerator is commenced with stirring and ice-cooling. The generation ofdiborane takes three hours and at the end of this period the apparatusis purged with nitrogen for thirty minutes and the tetrahydrofuransolution in the reaction vessel is heated under reflux for one hour. Thesolution is then cooled in ice and treated with 5 N HCl (100 ml.). Thesolvents are removed in vacuo and the resulting material dissolved inhot water, adjusted to a basic pH and extracted with ether. The extractis then worked up in the usual manner to give 3-(3- dimethylaminopropyl1 -phenyl-indoline.

In a similar manner as above the following compounds are prepared fromtheir corresponding indolinones:

S-(Z-dimethylaminoethyl)-l-phenyl-indoline hydrogen maleate3-[2-(N-benzyl-N-methylamino)ethyl]-l-phenyl-indoline3-[3-(N-benzyl-N-methylamino)propyl]-l-phenylindoline EXAMPLE IV3-(3-indolyl)propionic acid is hydrogenated at 4000 psi in the presenceof Raney nickel as described by Kornfeld, et. al. in J. Amer. Chem.Soc., vol. 78, page 3096 (1956). The resultant 3-(3-indolinyl)propionicacid is then phenylated by Ullman reaction with phenyl iodide and copperpowder to give l-phenyl-3-(3-indolinyl)propionic acid which is thenreacted with methylamine to form an amide. The amide is then reducedwith lithium aluminum hydride using standard reaction techniques andconditions to produce 3-(3- methyl-am inopropyl l -phenyl-indoline.

EXAMPLE V 3-(3-dimethylaminopropyl)-l-phenyl-2-indolinone (0.033 mol.)in dry xylene (75 ml.) is treated with ethyl chloroformate ml.) and themixture is warmed to 60-70 for an hour. An evolution of gas takes placeand more ethyl chloro-formate (10 ml.) is added and the heating iscontinued for one and a half hours. The excess of ethyl chloroformate isremoved by distillation and the volume of the reaction mixture ismaintained by the addition of dry xylene. The mixture is heated underreflux for four hours, cooled, extracted with 1 NHCl, washed with water,dried over anhydrous Na- .SO and evaporated. The resultant syrup isheated under reflux for l6-l 7 hours with a 40 percent solution ofhydrobromic acid in glacial acetic acid (50 ml.). The mixture isevaporated in vacuo and the resultant syrup is treated with water andether extracted to remove unreacted urethane. The aqueous layer isbasified with a cold aqueous solution of sodium carbonate and etherextracted. The ethereal extract is dried over magnesium sulfate,filtered and treated with an ethereal solution of HCl. 3-(3-methylaminopropyl)-l-phenyl-2-indolinone hydrochloride is obtained upon furtherrecrystallization.

EXAMPLE VI 3-[3- (N-benzyl-N-methylamino)propyl]-1-phenyl-2 -indolinone(0.4 mol.) is dissolved in absolute ethanol (650 ml.) and a solution ofpalladium chloride (6 g.) in water (40 ml.) containing sodium chloride(4 g.) is added. The mixture is cautiously treated with a solution ofsodium borohydride (6 g.) in water (40 ml.) over a period of ten minuteswith stirring. Stirring is continued for a further 15 minutes and the pHadjusted to l with concentrated hydrochloric acid. This mixture ishydrogenated at 50 psi and 60 for 16 hours by which time the theoreticalamount of hydrogen has been adsorbed. The mixture is filtered and thesolvent removed under reduced pressure. The residual oil is dissolved inwater (250 ml.), basified with 5 N sodium hydroxide solution andextracted with ether (4 X 200 ml.). The extracts are dried overmagnesium sulfate and treated with dry hydrogen chloride. The resultingproduct is further purified giving 3-(3-methylaminopropyl)-lphenyl-2-indolinone hydrochloride.

EXAMPLE VII 3 3-Methylamino-propyl )-l -phenyl-indole hydrochloride (1.5g.) is dissolved in water (5 ml.), basified with 5N NaOH and extractedinto ether. The

solvent is evaporated and the residual free base is taken into 10 ml. ofdry tetrahydrofuran. This solution is added to liquid ammonia ml.) and,while stirring under dry conditions, sodium (1 g.) is added in smallpieces, each piece after the first being added as soon as the blue colordisappeared. The reaction is taken to be complete when the blue colorpersisted for more than 7-l0 minutes. Solid ammonium chloride is thenadded and the ammonia is evaporated slowly. The final solution isevaporated in vacuo and the residual oil is taken up into dry ether.This solution is treated with ethereal oxalic acid solution and theprecipitated oxalate is recrystallized once from isopropanol-water toyield 1.2 g. of 3-(3-methylamino-propyl)-l-phenyl-indoline hydrogenoxalate. M. pt: l79-l 80 Calcd. for: C, H, N,O C, 67.39; H, 6.79; N,7.86

Found: C, 67.45; H, 6.75; N, 7.79

A small sample of the oxalate is converted into the free base and themass spectrum is obtained showing a molecular ion of 266, concordantwith the calculated molecular weight.

The compound prepared in Example V" has also been prepared according tothe following Example:

EXAMPLE vm 1. Ethyl 3-(3-indolyl)propionate (21.7 g., 0.1 mol) isdissolved in glacial acetic acid (250 ml.) and 2N HCl (50 ml., 0.1 mol)is added. This solution is hydrogenated at 60-70 and atmosphericpressure over a pre-reduced platinum oxide catalyst (20 g.), stirringcarefully throughout. The catalyst is then filtered off and the solutionis evaporated under reduced pressure to a thick oil. This is washed withether and the residual oil is carefully neutralized with Na CO solutionand extracted into ether. Evaporation of the dried ethereal extractsgives an oil which is distilled in vacuo at 150-155/0.2 mm. mercury toyield 19 g. of ethyl 3-(3- indolinyl)propionate.

2. Ethyl 3-(3-indolinyl-)propionate (15.33 g., 0.7 mol) is dissolved intetrahydrofuran (50 ml.) and this solution is added carefully to arefluxing solution of lithium aluminum hydride (3.8 g., 0.1 mol) intetrahydrofuran (200 ml.). The mixture is stirred and heated underreflux for 4 hours, and the complex is then destroyed by the addition of3.8 g. of water followed by 3.8 ml. of 5N NaOH. The inorganicprecipitate is filtered off and the solution evaporated to dryness whenit yielded a thick oil. This is distilled in vacuo at 180-2l0/0.2 mmmercury to yield 1 1.5 g. of 3-(3-indolinyl)propanol. I

3. To 3-(3-indolinyl)propanol (11.5 g., 0.065 mol) dissolved inhexamethyl phosphoramide (100 ml.), cuprous bromide (0.1 g.) andanhydrous K CO (13.9 g., 0.1 mol) are added. The mixture is heated to170 and bromobenzene (15.7 g., 0.1 mol) is added dropwise with stirring.The stirring and'heating at l70-180 is maintained for 6 hours, when itis poured into a large volume of water and extracted with ether. Theethereal liquors are dried over K CO and evaporated in vacuo to give athick oil, which is distilled in vacuo at 210- 220/0.1 mm. mercury toyield 10 g. of 1-phenyl-3-(3- indolinyl)propanol.

4. 1-Phenyl-3-(3-indolinyl)propanol (10 g., 0.044 mol) in dry benzene(50 ml.) is added to a cold mixture of pyridine (3.5 g., 0.044 mol) andp-toluenesulphonyl chloride (8.4 g., 0.044 mol) in benzene (50 ml.). Themixture is allowed to stand for 12 hours and then poured into water. Thebenzenic layer is dried over Na SO and treated with a large excess of 33percent ethanolic solution of methylamine (100 ml.) in a stainless steelbomb at 100 and left to stand for 12 hours.

The mixture is then evaporated to dryness and the residue basified with5N NaOH and extracted with ether. The ethereal solution is dried over NaCO and evaporated to yield an oil. This is taken up into dry ether andtreated with an ethereal solution of oxalic acid. The precipitate wasrecrystallized several times from isopropanol-water to give g. of pure3-(3- methylamino propyl)-l-phenyl-indoline hydrogen oxalate. M.P.179-180.

Analysis:

Calcd. for: C T-1 N 0 C, 67.39; H, 6.79; N, 7.86

Found: C, 67. ;H, 6. N, 7.

EXAMPLE IX Sulfuryl chloride (0.03 mol.) in glacial acetic acid (10 ml.)is added to a cooled solution of 3-(3-dimethylaminopropyl)-1-phenyl-2-indolinone hydrochloride (0.03 mol.) inglacial acetic acid ml.), the temperature being kept below 20. Themixture is stirred at room temperature for 2 hours, evaporated, adjustedto a basic pH and extracted into ether. The dried ethereal solution istreated with dry l-lCl gas and the resultant product, which may containsome 3-chloro-compound, is purified to give 5-chloro-3-(3dimethylaminopropyl)-1-phenyl-2indolinone hydrochloride.

EXAMPLE X EXAMPLE XI Stable tablets and capsules of 3-( 3-dimethylaminopropyl)-1-phenyl-2-indolinone hydrochloride are made asfollows:

Tablets mg tablet 3-(3-dimethylaminopropyU-1-phenyl-2- indolinonehydrochloride 10.0 Dicalcium phosphate 120.0 Com starch 20.0 Magnesiumstearate 1.6 Sodium laurylsulfate 0.2

The ingredients are blended and compressed into tablets. These tabletsare then broken into granules and recompressed into finished tablets.

Capsule mg capsule 3-(3-dimethylaminopropyl)-1-phenyl-2- indolinonehydrochloride 10.0 Corn starch 127.0 Microcrystalline cellulose 127.0Magnesium stearate 5.4 Sodium laurylsulfate 0.6

The ingredients are blended and filled into a hard gelatine capsule ofsuitable size.

EXAMPLE X11 Following the procedure of Example 1 but using sodamide orsodium hydride in place of thallous ethoxide, substantial amounts of3,3-bis(3- dimethylaminopropyl)-1-phenyl-2-indolinone is formed. Thisindicates that this procedure is unsuitable for the preparation of3-mono-substituted derivatives.

EXAMPLE Xlll The products of Examples 1 and V11 have been evaluated inseveral different tests designed to show that they have properties incommon with known antidepressant drugs. The results of these tests anddetails of the test systems are shown in the following Table and thenotes appended thereto.

In the Table, comparative results are also given for the3-methyl-substituted analogs of the products of Examples I and VII.These 3-methyl-substituted analogs are the products of Examples I and Xof both our copending application See. No. 706672 filed Feb. 19, 1968and now abandoned and our copending application Ser. No. 718,943 filedApr. 4, 1968 and now U.S. Pat. No. 3,574,232, and are identified in theExample XIII of each of these applications as compound (b) of The ratingof activity for the above tests is as follows: inactive slightly activeH- moderately active +-llvery active The test systems were as follows:

1. Potentiation of amphetamine-induced excitation in the rat 25mg/Kg oftest compound administered orally cf. Quinton,et al, Nature, 200, 178(1963).

2. Antagonism of tetrabenazine-induced sedation in the rat 50mg/Kgfollowed by a further 20mg/Kg, administered orally cf. Sulser, et al.,J.Pharm.Exp.Therap., 144, 321 (1964).

3. Antagonism of reserpine-induced hypothermia in the mouse IOmg/Kgadministered intraperitoneally, 18 hours after subcutaneous injection ofreserpinecf. Askew, Life Science, 2, 723

. Antagonism of norepinephrine-induced hypothermia in the mouse IOmg/Kgfollowed by a further IOmg/Kg, administered orally, followed byintra-ventricular injection of norepinephrine cf. Brittain, J.Pharm.Pharmac., 18, 621 (1966).

5. Potentiation of low-frequency electrical stimulation of thenictitating membrane of the cat, after doses ranging from 0.5 to Smg/Kgof test compound, administered intravenously cf. Thoenen,

et al., I-Ielv.physiol. Acta, 22, (1964).

6. Potentiation of the effect of injected norepinephrine on the bloodpressure of the cat, after the same dosages of test compound as in test(5) cf. Halliwell et al., Brit.J.Pharmacol., 23, 330 (1964).

The results of the tests show that, in the three tests carried out onit, the product of Example I had a high degree of activity, while ineach test it was more active than its S-methyl analog. Similarly, infive out of the six tests carried out on it, the product of Example VIIhad a high degree of activity, while in three of the tests it wassignificantly more active than its 3-methyl analog, in two further testsit was equally as active, and in the sixth test it was only marginallyless active than its 3- methyl analog.

What is claimed is:

l. A composition in dosage unit form useful for alleviating mentaldepression in a host comprising a pharmaceutical carrier and from about5 mg. to about 500 mg. of a compound selected from the group consistingof those of the formula:

wherein R and R are each selected from the group consisting of hydrogen,alkyl of from one to four carbon atoms, benzyl and R and R when takentogether, complete a ring selected from the group consisting ofpiperidine, pyrrolidino, morpholino, piperazino, N- benzylpiperazino,N-alkylpiperazino and N'-hydroxyalkylpiperazino, said alkyl containingfrom one to four carbon atoms; R is selected from the group consistingof hydrogen, nitro and halogen, (F, Cl, Br, I); X is selected from thegroup consisting of two hydrogen atoms and an oxygen atom; n is aninteger of from 2 to 4 and pharmaceutically acceptable acid additionsalts thereof.

2. A composition as claimed in claim 1 wherein R is hydrogen, n is 3, Xis oxygen and R and R are methyl.

3. A composition as claimed in claim 1 wherein R is hydrogen, n is 3, Xis 2 hydrogen atoms, R is methyl and R is hydrogen.

4. A composition as claimed in claim 1 wherein X is two hydrogen atoms.

5. A composition as claimed in claim 4 wherein R is methyl and R ishydrogen.

i i t

1. A composition in dosage unit form useful for alleviating mentaldepression in a host comprising a pharmaceutical carrier and from about5 mg. to about 500 mg. of a compound selected from the group consistingof those of the formula:
 2. A composition as claimed in claim 1 whereinR3 is hydrogen, n is 3, X is oxygen and R1 and R2 are methyl.
 3. Acomposition as claimed in claim 1 wherein R3 is hydrogen, n is 3, X is 2hydrogen atoms, R2 is methyl and R1 is hydrogen.
 4. A composition asclaimed in claim 1 wherein X is two hydrogen atoms.